ABSTRACT
Oritavancin displayed potent and stable activity (MIC90 range of 0.06 to 0.5 mg/L) over a 10-year period (2010 to 2019) against Gram-positive pathogens that cause bloodstream infections (BSI), including methicillin-resistant Staphylococcus aureus (MRSA) and resistant subsets of Enterococcus spp. Daptomycin and linezolid were also active against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus (VRE). Only oritavancin and linezolid remained active against Enterococcus faecium isolates displaying an elevated daptomycin MIC (i.e., 2 to 4 mg/L). Proportions of methicillin-resistant S. aureus and vancomycin-resistant Enterococcus within the respective S. aureus and enterococcal populations decreased over this period.
KEYWORDS: lipoglycopeptides, E. faecium, VRE, VanA, VanB, vancomycin resistance, daptomycin resistance
INTRODUCTION
Bloodstream infections (BSI) are a major cause of morbidity and mortality among healthcare- and community-associated infections. In this scenario, the emergence and global spread of multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), and carbapenem-resistant Enterobacterales imposes a serious challenge for treating BSI caused by these pathogens (1–3).
Oritavancin is a lipoglycopeptide agent with a prolonged half-life and concentration-dependent bactericidal activity against clinically relevant Gram-positive pathogens (4). Previous studies have demonstrated that, in addition to acting against methicillin-susceptible S. aureus (MSSA), streptococci, and vancomycin-susceptible enterococci isolates, oritavancin shows potent activity against resistant isolates, such as MRSA and VRE (5–8).
The efficacy and safety of a single 1,200-mg dose of oritavancin over a 3-h infusion (Orbactiv) was demonstrated previously in clinical trials (SOLO I and SOLO II studies) for treating patients with acute bacterial skin and skin structure infection (ABSSSI) (4, 9, 10). More recently, the same oritavancin dose (1,200 mg) with a shorter infusion duration time (1 h; Kimyrsa) was approved by the US FDA (11, 12), providing additional flexibility in treating patients with moderate or severe ABSSSI. This study evaluated the activity of oritavancin against a collection of Gram-positive pathogens and resistant subsets causing BSI in US medical during a 10-year (2010 to 2019) period. This study expands on a previous analysis of oritavancin activity against US and European Enterococcus species isolates during 2011 to 2014 (5).
Throughout 2010 to 2019, 15,403 Gram-positive bacterial pathogens causing BSI (1 per patient episode) were collected from 36 medical centers across all 9 US Census Divisions. Bacterial confirmatory identification was performed by JMI Laboratories (North Liberty, IA) using matrix-assisted light desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and standard microbiology methods, such as bile solubility and susceptibility to optochin (see the Table 1 footnotes for a list of all isolates included in the study). Susceptibility testing was performed by broth microdilution following CLSI methods (13), using either dry-form (2010 to 2014) (Thermo Fisher; Bedford, MA) or frozen-form (2015 to 2019) panels (JMI Laboratories). MIC interpretations were based on CLSI criteria (14).
TABLE 1.
Oritavancin activity and occurrence of resistance phenotypes among Gram-positive isolates that cause BSI in US medical centers (2010 to 2019)a
| Organism or organism group (no. of isolates) | Oritavancin MIC50/MIC90 (mg/L) and % susceptible (CLSIb) per yr group |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2010–2011 |
2012–2013 |
2014–2015 |
2016–2017 |
2018–2019 |
All yrs |
MIC range (mg/L) | |||||||
| MIC50/MIC90 | %S | MIC50/MIC90 | %S | MIC50/MIC90 | %S | MIC50/MIC90 | %S | MIC50/MIC90 | %S | MIC50/MIC90 | %S | ||
| S. aureus (7,498) | 0.03/0.06 | 99.5 | 0.03/0.06 | 100.0 | 0.015/0.06 | 99.9 | 0.015/0.06 | 99.9 | 0.03/0.06 | 99.9 | 0.03/0.06 | 99.8 | ≤0.008–0.25 |
| MRSA (3,226) | 0.03/0.06 | 99.8 | 0.03/0.06 | 100.0 | 0.015/0.06 | 99.8 | 0.015/0.06 | 99.7 | 0.03/0.06 | 100.0 | 0.03/0.06 | 99.8 | ≤0.008–0.25 |
| MSSA (4,272) | 0.03/0.06 | 99.2 | 0.03/0.06 | 100.0 | 0.015/0.06 | 100.0 | 0.015/0.06 | 100.0 | 0.03/0.06 | 99.9 | 0.03/0.06 | 99.8 | ≤0.008–0.25 |
| CoNSc (1,872) | 0.03/0.06 | 99.4 | 0.03/0.06 | 100.0 | 0.03/0.06 | 99.8 | 0.03/0.12 | 98.5 | 0.06/0.12 | 95.3 | 0.03/0.12 | 98.4 | ≤0.008–1 |
| MRCoNS (1,163) | 0.03/0.06 | 99.5 | 0.03/0.06 | 100.0 | 0.03/0.06 | 99.6 | 0.03/0.12 | 97.5 | 0.06/0.12 | 94.0 | 0.03/0.12 | 97.9 | ≤0.008–0.5 |
| MSCoNS (709) | 0.015/0.06 | 99.2 | 0.015/0.06 | 100.0 | 0.03/0.06 | 100.0 | 0.03/0.06 | 100.0 | 0.03/0.06 | 97.0 | 0.03/0.06 | 99.2 | ≤0.008–1 |
| VGSd (921) | 0.015/0.12 | 100.0 | ≤0.008/0.06 | 100.0 | 0.015/0.06 | 100.0 | 0.015/0.25 | 99.3 | 0.015/0.25 | 93.8 | 0.015/0.12 | 98.7 | ≤0.008–0.5 |
| BHSe (1,394) | 0.03/0.12 | 100.0 | 0.03/0.12 | 99.1 | 0.03/0.12 | 98.6 | 0.06/0.25 | 97.1 | 0.06/0.25 | 98.2 | 0.03/0.25 | 98.5 | ≤0.008–1 |
| Enterococcus spp. (2,895) | 0.015/0.06 | 97.0 | 0.015/0.03 | 98.0 | 0.015/0.06 | 98.1 | 0.015/0.03 | 99.4 | 0.015/0.06 | 98.1 | 0.015/0.06 | 97.9 | ≤0.008–0.5 |
| E. faecalis (1,709) | 0.015/0.06 | 96.2 | 0.015/0.03 | 97.4 | 0.015/0.03 | 98.3 | 0.015/0.03 | 99.1 | 0.015/0.03 | 97.8 | 0.015/0.06 | 97.5 | ≤0.008–0.5 |
| Vancomycin-NS (≥8 mg/L) (62) | 0.25/0.5 | 33.3 | 0.25/- | 28.6 | 0.12/- | 50.0 | 0.12/0.25 | 75.0 | 0.25/- | 12.5 | 0.25/0.5 | 40.3 | 0.008–0.5 |
| VanA phenotype (53) | 0.25/0.5 | 25.0 | 0.25/- | 16.7 | 0.25/- | 20.0 | 0.12/0.25 | 75.0 | 0.25/- | 12.5 | 0.25/0.5 | 32.7 | 0.015–0.5 |
| VanB phenotype (9) | 0.015/- | 100.0 | 0.015 | 100.0 | 0.015/- | 100.0 | - | - | - | - | 0.015/- | 100.0 | 0.008–0.25 |
| Daptomycin-NS (≥4 mg/L) (8) | 0.03/- | 100.0 | 0.03/- | 100.0 | 0.015/- | 100.0 | 0.03 | 100.0 | - | - | 0.03/- | 100.0 | 0.008–0.06 |
| Linezolid-NS (≥4 mg/L) (2) | ≤0.008 | 100.0 | - | - | - | - | - | - | 0.008 | 100.0 | ≤0.008/- | 100.0 | ≤0.008 |
| E. faecium (1,082) | 0.03/0.12 | 98.0 | 0.03/0.12 | 98.6 | 0.015/0.12 | 97.6 | 0.015/0.06 | 100.0 | 0.015/0.06 | 98.4 | 0.03/0.06 | 98.4 | ≤0.008–0.5 |
| Vancomycin-NS (≥8 mg/L) (784) | 0.03/0.12 | 97.5 | 0.03/0.12 | 98.2 | 0.03/0.12 | 96.5 | 0.03/0.06 | 100.0 | 0.03/0.06 | 97.4 | 0.03/0.12 | 97.8 | ≤0.008–0.5 |
| VanA phenotype (755) | 0.03/0.12 | 97.5 | 0.03/0.12 | 98.2 | 0.03/0.12 | 96.3 | 0.03/0.06 | 100.0 | 0.03/0.06 | 97.4 | 0.03/0.12 | 97.0.8 | ≤0.008–0.5 |
| VanB phenotype (29) | ≤0.008/≤0.008 | 100.0 | ≤0.008/- | 100.0 | ≤0.008/- | 100.0 | - | - | ≤0.008/- | 100.0 | ≤0.008/0.03 | 100.0 | ≤0.008–0.06 |
| Daptomycin-R (≥8 mg/L) (9) | ≤0.008/- | 100.0 | - | - | ≤0.008/- | 100.0 | 0.015/- | 100.0 | 0.06/- | 66.7 | 0.015/- | 88.9 | ≤0.008–0.25 |
| Daptomycin MIC, 2–4 mg/L (540) | 0.03/0.12 | 97.2 | 0.03/0.12 | 98.9 | 0.03/0.12 | 97.5 | 0.015/0.06 | 100.0 | 0.015/0.06 | 96.6 | 0.03/0.12 | 97.8 | ≤0.008–0.5 |
| Linezolid-NS (≥4 mg/L) (13) | ≤0.008/- | 100.0 | 0.03 | 100.0 | 0.12 | 100.0 | 0.015/- | 100.0 | ≤0.008/- | 100.0 | 0.015/0.06 | 100.0 | ≤0.008–0.12 |
| Ampicillin-R (≥16 mg/L) (945) | 0.03/0.12 | 97.9 | 0.03/0.12 | 98.5 | 0.03/0.12 | 97.2 | 0.015/0.06 | 100.0 | 0.03/0.06 | 97.9 | 0.03/0.12 | 98.2 | ≤0.008–0.5 |
| Other Enterococcus spp.f (104) | ≤0.008/0.015 | 100.0 | ≤0.008 | 100.0 | ≤0.008/0.03 | 100.0 | ≤0.008/0.015 | 100.0 | ≤0.008/0.015 | 100.0 | ≤0.008/0.015 | 100.0 | ≤0.008–0.06 |
MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; MRCoNS, methicillin-resistant coagulase-negative Staphylococcus; MSCoNS, methicillin-susceptible coagulase-negative Staphylococcus; VGS, Viridans group streptococci; BHS, beta-hemolytic streptococci; R, resistant; NS, nonsusceptible.
Using CLSI (14) breakpoints. The oritavancin-susceptible breakpoint for S. aureus was applied to CoNS. The oritavancin-susceptible breakpoint for vancomycin-susceptible E. faecalis was applied to all Enterococcus species isolates.
Organisms included: Staphylococcus arlettae (1), S. auricularis (14), S. capitis (115), S. caprae (10), S. cohnii (10), S. condimenti (1), S. epidermidis (1,133), S. haemolyticus (80), S. hominis (220), S. intermedius (1), S. lugdunensis (64), S. pasteuri (2), S. pettenkoferi (21), S. pseudintermedius (3), S. saprophyticus (10), S. schleiferi (4), S. sciuri (1), S. simulans (15), S. warneri (36), and Staphylococcus spp. (131).
Organisms included: Streptococcus alactolyticus (2), S. anginosus group (89), S. australis (6), S. bovis group (28), S. constellatus (11), S. cristatus (7), S. equinus (1), S. gallolyticus (41), S. gordonii (23), S. infantarius (1), S. infantis (5), S. intermedius (12), S. lutetiensis (10), S. mitis group (393), S. mutans (12), S. parasanguinis (61), S. salivarius group (75), S. sanguinis (52), S. sinensis (1), S. vestibularis (9), and viridans group Streptococcus spp. (82).
Organisms included: Streptococcus agalactiae (747), S. canis (7), S. dysgalactiae (143), S. equi (1), and S. pyogenes (496).
Organisms included: Enterococcus avium (15), E. casseliflavus (23), E. durans (9), E. gallinarum (33), E. hirae (8), E. raffinosus (12), and Enterococcus spp. (4).
S. aureus (48.7%) alone comprised almost half of Gram-positive pathogens. The proportion of methicillin resistance among S. aureus varied from 46.6% to 42.3%, and these rates appeared to trend lower over time (Table 2). This trend was also noted in other regional and national surveillance programs during the 2000s, likely as a result of an increasing emphasis on hospital infection prevention, stewardship programs, and activities directed toward healthcare quality improvement (2, 15–18). Similarly, a progressive decrease in the rate of methicillin resistance among coagulase-negative Staphylococcus (MRCoNS) BSI was noted. Oritavancin MIC50 values against S. aureus ranged from 0.015 to 0.03 mg/L, and MIC90 values were 0.06 mg/L irrespective of methicillin susceptibility (Table 1). Oritavancin susceptibility rates of >99.5% were observed during this period for S. aureus (99.5% in 2010 to 2011). Oritavancin displayed MIC50 values of 0.03 to 0.06 mg/L against CoNS. Oritavancin inhibited 98.4% to 100.0% of CoNS isolates at ≤0.12 mg/L, except during 2018 to 2019 (95.3% susceptible). Oritavancin susceptibility remained stable (>95%) across the years against MSSA, MRSA, methicillin-susceptible CoNS, and MRCoNS, and was comparable to vancomycin, daptomycin, and linezolid (see Table S1 in the supplemental material).
TABLE 2.
Evolution of resistance phenotypes of Staphylococcus spp. and Enterococcus species isolates from BSI in US medical centersa
| Rates of resistance (%) per study periodb |
||||||
|---|---|---|---|---|---|---|
| Resistance phenotype | 2010–2011 | 2012–2013 | 2014–2015 | 2016–2017 | 2018–2019 | All yrs |
| MRSA | 46.6 | 40.1 | 43.7 | 40.4 | 42.3 | 43.0 |
| MRCoNS | 64.3 | 62.9 | 64.7 | 61.4 | 58.3 | 62.1 |
| E. faecalis | ||||||
| VRE (≥8 mg/L) | 4.5 | 3.6 | 3.4 | 3.7 | 2.2 | 3.6 |
| VanA phenotype | 81.5 | 85.7 | 62.5 | 100.0 | 100.0 | 85.5 |
| VanB phenotype | 18.5 | 14.3 | 37.5 | 0.0 | 0.0 | 14.5 |
| E. faecium | ||||||
| VRE (≥8 mg/L) | 79.6 | 77.4 | 67.7 | 66.5 | 62.8 | 72.5 |
| VanA phenotype | 96.6 | 98.2 | 95.5 | 96.7 | 93.9 | 96.3 |
| VanB phenotype | 3.4 | 1.8 | 4.5 | 3.3 | 6.1 | 3.7 |
| Daptomycin-R (≥8 mg/L) | 0.5 | 0.0 | 1.2 | 1.1 | 1.6 | 0.8 |
| Daptomycin MIC, 2–4 mg/L | 62.4 | 60.3 | 48.2 | 33.5 | 31.7 | 49.9 |
| Linezolid-NS (≥4 mg/L) | 1.7 | 0.7 | 0.6 | 1.1 | 1.1 | 1.2 |
| Ampicillin-R (≥16 mg/L) | 92.6 | 90.4 | 87.2 | 81.3 | 79.2 | 87.3 |
MRSA, methicillin-resistant Staphylococcus aureus; MRCoNS, methicillin-resistant coagulase-negative Staphylococcus; VRE, vancomycin-resistant Enterococcus; R, resistant; NS, nonsusceptible.
Using CLSI (14) breakpoints.
Enterococcus spp. comprised 18.8% (2,895 out of 15,403) of Gram-positive pathogens causing BSI, where E. faecalis was the most common species (59.0%), followed by E. faecium (37.4%). VRE rates within E. faecalis decreased over time, from 4.5% (2010 to 2011) to 2.2% (2018 to 2019). Likewise, vancomycin resistance (from 79.6% to 62.8%) and ampicillin resistance (from 92.6% to 79.2%) decreased in E. faecium (Table 2). Ampicillin resistance and VRE phenotypes were displayed by most E. faecium (87.3% were ampicillin resistant and 72.5% were VRE), whereas only 3.6% of E. faecalis were resistant to vancomycin and none were resistant to ampicillin (Table S2). The decline in VRE as a proportion of total enterococcal infections may be due to the same reasons as described above for MRSA (2, 19). The past increase in VRE in the US was mostly due to the expansion of E. faecium clonal complex 17 (20). The increase in ampicillin and vancomycin susceptibility may indicate a change in the epidemiology of E. faecium causing BSI in the United States. However, this epidemiology information was not captured for this large collection.
Oritavancin activity against E. faecalis and E. faecium was stable between 2010 and 2019. Consistent MIC50 values of 0.015 mg/L and MIC90 values of 0.03 to 0.06 mg/L were observed in all years against E. faecalis. Oritavancin inhibited 96.2% (in 2010 to 2011) to 99.1% (in 2016 to 2017) of E. faecalis at ≤0.12 mg/L (Table 1). E. faecium displayed MIC50/MIC90 values of 0.03/0.12 mg/L during the 2010–2011 and 2012–2013 periods, whereas MIC50/MIC90 values of 0.015/0.06 mg/L were seen during the 2016–2017 and 2018–2019 periods. Oritavancin susceptibility rates remained stable against E. faecium across all time periods (97.6% to 98.6%). Many antimicrobials showed activity (>95%) against E. faecalis, such as ampicillin, daptomycin, linezolid, vancomycin, and oritavancin, while only daptomycin, linezolid, and oritavancin remained active against E. faecium (Table S2).
Oritavancin inhibited 97.7% of VanA and 100% of VanB E. faecium at ≤0.12 mg/L. In contrast, only 32.7% of E. faecalis isolates displaying the VanA phenotype were inhibited by oritavancin at ≤0.12 mg/L. VRE E. faecalis showed oritavancin MIC50 values ranging from 0.12 to 0.25 mg/L, whereas MIC50 values ranged from 0.015 to 0.03 mg/L against VRE E. faecium. The greater activity of oritavancin against E. faecium compared to E. faecalis is not well understood. Expression of vanZ or changes in LiaS sensor kinase were reported as possible explanations (21).
Almost half (49.9%) of E. faecium displayed daptomycin MICs of 2 to 4 mg/L, and 9 (0.8%) isolates were resistant (MIC, ≥8 mg/L; Table 1). The rates of E. faecium displaying elevated daptomycin MICs showed a progressive decrease over the study years, ranging from 62.4% (in 2010 to 2011) to 31.7% (in 2018 to 2019) (Table 2). Oritavancin activity against E. faecium with elevated MIC values against daptomycin (2 to 4 mg/L) remained stable throughout the study (MIC50/MIC90, 0.015 to 0.03/0.06 to 0.12 mg/L). Oritavancin inhibited >97% of VRE, linezolid-nonsusceptible, and E. faecium displaying elevated daptomycin MICs (2 to 4 mg/L) at ≤0.12 mg/L. Recent pharmacokinetic (PK) analysis provide evidence that multiple oritavancin doses may be beneficial in treating severe infections and can achieve serum concentrations above the E. faecalis susceptibility breakpoint of 0.12 mg/L, for over 4 weeks (22, 23). However, clinical studies are needed to evaluate the relationship between PK and clinical outcomes with oritavancin treatment. Another study conducted by Belley and colleagues on the pharmacodynamic activity of oritavancin against daptomycin-nonsusceptible VRE E. faecium suggested that a multiple-dose strategy with oritavancin may be effective against daptomycin-nonsusceptible vancomycin-resistant E. faecium (24).
Viridans group Streptococcus isolates displayed oritavancin MIC50/MIC90 values of ≤0.008 to 0.015/0.06 to 0.25 mg/L and susceptibility rates of 93.8% to 100.0% over the study period, while beta-hemolytic Streptococcus showed oritavancin MIC50/MIC90 values of 0.03 to 0.06/0.12 to 0.25 mg/L and susceptibility rates of 97.1% to 100.0%. The activity of oritavancin and comparator agents against Viridans group Streptococcus and beta-hemolytic Streptococcus are displayed in the supplemental material (Table S1).
In conclusion, we noted encouraging decreasing trends in MRSA and VRE rates. Oritavancin showed potent and consistent activity against Gram-positive pathogens that cause BSI in US from 2010 to 2019, including multidrug-resistant pathogens such as MRSA, MRCoNS, VRE, and E. faecium with elevated daptomycin MIC and reduced susceptibility to linezolid and daptomycin. Further studies are warranted to identify appropriate oritavancin dosing strategies and the role of oritavancin in the armamentarium against either susceptible or multidrug-resistant Gram-positive isolates causing BSI and other severe infections.
ACKNOWLEDGMENTS
We thank the following staff members at JMI Laboratories (North Liberty, IA, USA): A. Chen, M. Konrardy, J. Maher, M. Janechek, and J. Oberholser for technical support and/or assistance with manuscript preparation.
This study was performed by JMI Laboratories and supported by Melinta Therapeutics, Inc., which included funding for services related to preparing the manuscript.
JMI Laboratories contracted to perform services in 2020 for Affinity Biosensors, Allergan, Amicrobe, Inc., Amplyx Pharma, Artugen Therapeutics USA, Inc., Astellas, Basilea, Beth Israel Deaconess Medical Center, BIDMC, bioMérieux, Inc., BioVersys Ag, Bugworks, Cidara, Cipla, Contrafect, Cormedix, Crestone, Inc., Curza, CXC7, Entasis, Fedora Pharmaceutical, Fimbrion Therapeutics, Fox Chase, GlaxoSmithKline, Guardian Therapeutics, Hardy Diagnostics, IHMA, Janssen Research & Development, Johnson & Johnson, Kaleido Biosciences, KBP Biosciences, Luminex, Matrivax, Mayo Clinic, Medpace, Meiji Seika Pharma Co., Ltd., Melinta, Menarini, Merck, Meridian Bioscience Inc., Micromyx, MicuRx, N8 Medical, Nabriva, National Institutes of Health, National University of Singapore, North Bristol NHS Trust, Novome Biotechnologies, Paratek, Pfizer, Prokaryotics Inc., QPEX Biopharma, Rhode Island Hospital, RIHML, Roche, Roivant, Salvat, Scynexis, SeLux Diagnostics, Shionogi, Specific Diagnostics, Spero, SuperTrans Medical LT, T2 Biosystems, The University of Queensland, Thermo Fisher Scientific, Tufts Medical Center, Universite de Sherbrooke, University of IA, University of IA Hospitals and Clinics, University of Wisconsin, UNT System College of Pharmacy, URMC, UT Southwestern, VenatoRx, Viosera Therapeutics, and Wayne State University.
There are no speakers’ bureaus or stock options to declare.
Footnotes
Supplemental material is available online only.
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